The tumor suppressor gene p53 is a paradigm for multi-functional regulator of processes ranging from proliferation to replicative senescence and apoptosis. P53 is the most commonly afflicted gene in human cancers, and its loss of function can be an early or late event in the malignant process. Thus, detailed investigators of its normal effector pathways and their interactions as well as mechanisms affecting p53 regulation are critical to understand of the role of p53 loss in cancer as well as efforts to intervene in this process. The four projects in this Program focus on the cellular responses to p53 which have been implicated in growth arrest, apoptosis, or senescence. This program brings together a unique group of investigators representing a variety of disciplines and approaches ranging from studies on protein stability to developmental biology. Many have recently come to Mount Sinai as part of a major initiative to expand the cancer research enterprise at this Institution. Four of the six Investigators (Aaronson, Ronai, Licht and Sassoon) have recently become actively involved in studies relative to p53. Thus they bring new perspectives to this field which has already led to new hypotheses and a broader understanding of p53 pathways. Thus they bring new perspectives to this field which has already led to new hypotheses and a broader understanding of p53 pathways. Accordingly, this unique combination of perspectives will focus on the elucidation of a new understanding of mechanisms underlying the ability of p53 to exercise its multiple functions. The specific problems addressed are: how p53 regulates cellular senescence (Project 1); identifying mechanisms underlying the regulation of p53 stability (Project 2); elucidating convergent roles of BRCA1 and p53 in gene expression (Project 3); and the mechanisms by which a p53-regulated genes, P21 and Siah1, dictate cell survival and death pathways (Project 4). Our proposal contains collaborations utilizing shared reagents and resources which enable us to address endpoints that would not be reached by any single project.. The proposed work will benefit from a core facility, knockout cell culture, which will enable us to make rapid progress on each of our collective Aims. This critical mass was formed to address a focused set of innovative hypotheses, which will provide new understanding of mechanisms concerning the multiple functions exerted by the tumor suppressor p53.